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American Journal of Transplantation :... Jun 2016Liver transplantation, either a partial liver from a living or deceased donor or a whole liver from a deceased donor, is the only curative therapy for severe end-stage... (Review)
Review
Liver transplantation, either a partial liver from a living or deceased donor or a whole liver from a deceased donor, is the only curative therapy for severe end-stage liver disease. Only one-third of those on the liver transplant waiting list will be transplanted, and the demand for livers is projected to increase 23% in the next 20 years. Consequently, organ availability is an absolute constraint on the number of liver transplants that can be performed. Regenerative therapies aim to enhance liver tissue repair and regeneration by any means available (cell repopulation, tissue engineering, biomaterials, proteins, small molecules, and genes). Recent experimental work suggests that liver repopulation and engineered liver tissue are best suited to the task if an unlimited availability of functional induced pluripotent stem (iPS)-derived liver cells can be achieved. The derivation of iPS cells by reprogramming cell fate has opened up new lines of investigation, for instance, the generation of iPS-derived xenogeneic organs or the possibility of simply inducing the liver to reprogram its own hepatocyte function after injury. We reviewed current knowledge about liver repopulation, generation of engineered livers and reprogramming of liver function. We also discussed the numerous barriers that have to be overcome for clinical implementation.
Topics: Animals; Humans; Liver Diseases; Liver Regeneration; Liver Transplantation; Tissue Engineering
PubMed: 26699680
DOI: 10.1111/ajt.13678 -
Medical Science Monitor : International... Dec 2020Liver regeneration (LR) is a set of complicated mechanisms between cells and molecules in which the processes of initiation, maintenance, and termination of liver repair... (Review)
Review
Liver regeneration (LR) is a set of complicated mechanisms between cells and molecules in which the processes of initiation, maintenance, and termination of liver repair are regulated. Although LR has been studied extensively, there are still numerous challenges in gaining its full understanding. Cells for LR have a wide range of sources and the feature of plasticity, and regeneration patterns are not the same under different conditions. Many patients undergoing partial hepatectomy develop cirrhosis or steatosis. The changes of LR in these cases are not clear. Many types of cells participate in LR. Hepatocytes, biliary epithelial cells, hepatic progenitor cells, and human liver stem cells can serve as the cell sources for LR. However, different types and degrees of damage trigger the response from the most suitable cells. Exploring the cell sources of LR is of great significance for accelerating recovery of liver function under different pathological patterns and developing a cell therapy strategy to cope with the shortage of donors for liver transplantation. In clinical practice, the background of the liver influences regeneration. Fibrosis and steatosis create different LR microenvironments and signal molecule interaction patterns. In addition, factors such as partial hepatectomy, aging, platelets, nerves, hormones, bile acids, and gut microbiota are widely involved in this process. Understanding the influencing factors of LR has practical value for individualized treatment of patients with liver diseases. In this review, we have summarized recent studies and proposed our views. We discuss cell sources and the influential factors on LR to help in solving clinical problems.
Topics: Animals; Gastrointestinal Microbiome; Hepatocytes; Humans; Liver Regeneration; Signal Transduction; Stem Cell Niche; Stem Cells
PubMed: 33311428
DOI: 10.12659/MSM.929129 -
Cell Communication and Signaling : CCS Aug 2022The liver is unique in its ability to regenerate from a wide range of injuries and diseases. Liver regeneration centers around hepatocyte proliferation and requires the... (Review)
Review
The liver is unique in its ability to regenerate from a wide range of injuries and diseases. Liver regeneration centers around hepatocyte proliferation and requires the coordinated actions of nonparenchymal cells, including biliary epithelial cells, liver sinusoidal endothelial cells, hepatic stellate cells and kupffer cells. Interactions among various hepatocyte and nonparenchymal cells populations constitute a sophisticated regulatory network that restores liver mass and function. In addition, there are two different ways of liver regeneration, self-replication of liver epithelial cells and transdifferentiation between liver epithelial cells. The interactions among cell populations and regenerative microenvironment in the two modes are distinct. Herein, we first review recent advances in the interactions between hepatocytes and surrounding cells and among nonparenchymal cells in the context of liver epithelial cell self-replication. Next, we discuss the crosstalk of several cell types in the context of liver epithelial transdifferentiation, which is also crucial for liver regeneration. Video abstract.
Topics: Endothelial Cells; Hepatic Stellate Cells; Hepatocytes; Liver; Liver Regeneration
PubMed: 35941604
DOI: 10.1186/s12964-022-00918-z -
Hepatology Communications Mar 2021The hepatic mesenchyme has been studied extensively in the context of liver fibrosis; however, much less is known regarding the role of mesenchymal cells during liver... (Review)
Review
The hepatic mesenchyme has been studied extensively in the context of liver fibrosis; however, much less is known regarding the role of mesenchymal cells during liver regeneration. As our knowledge of the cellular and molecular mechanisms driving hepatic regeneration deepens, the key role of the mesenchymal compartment during the regenerative response has been increasingly appreciated. Single-cell genomics approaches have recently uncovered both spatial and functional zonation of the hepatic mesenchyme in homeostasis and following liver injury. Here we discuss how the use of preclinical models, from in vivo mouse models to organoid-based systems, are helping to shape our understanding of the role of the mesenchyme during liver regeneration, and how these approaches should facilitate the precise identification of highly targeted, pro-regenerative therapies for patients with liver disease.
Topics: Animals; Cells, Cultured; Hepatic Stellate Cells; Humans; Liver; Liver Diseases; Liver Regeneration; Mesoderm; Mice
PubMed: 33681672
DOI: 10.1002/hep4.1628 -
Cellular and Molecular Life Sciences :... Apr 2018The prevalence of liver diseases is increasing globally. Orthotopic liver transplantation is widely used to treat liver disease upon organ failure. The complexity of... (Review)
Review
The prevalence of liver diseases is increasing globally. Orthotopic liver transplantation is widely used to treat liver disease upon organ failure. The complexity of this procedure and finite numbers of healthy organ donors have prompted research into alternative therapeutic options to treat liver disease. This includes the transplantation of liver cells to promote regeneration. While successful, the routine supply of good quality human liver cells is limited. Therefore, renewable and scalable sources of these cells are sought. Liver progenitor and pluripotent stem cells offer potential cell sources that could be used clinically. This review discusses recent approaches in liver cell transplantation and requirements to improve the process, with the ultimate goal being efficient organ regeneration. We also discuss the potential off-target effects of cell-based therapies, and the advantages and drawbacks of current pre-clinical animal models used to study organ senescence, repopulation and regeneration.
Topics: Animals; Cell Differentiation; Cell- and Tissue-Based Therapy; Humans; Liver; Liver Diseases; Liver Regeneration; Liver Transplantation; Pluripotent Stem Cells
PubMed: 29181772
DOI: 10.1007/s00018-017-2713-8 -
Proceedings of the National Academy of... Jul 2022Liver regeneration is a well-orchestrated process that is typically studied in animal models. Although previous animal studies have offered many insights into liver...
Liver regeneration is a well-orchestrated process that is typically studied in animal models. Although previous animal studies have offered many insights into liver regeneration, human biology is less well understood. To this end, we developed a three-dimensional (3D) platform called structurally vascularized hepatic ensembles for analyzing regeneration (SHEAR) to model multiple aspects of human liver regeneration. SHEAR enables control over hemodynamic alterations to mimic those that occur during liver injury and regeneration and supports the administration of biochemical inputs such as cytokines and paracrine interactions with endothelial cells. We found that exposing the endothelium-lined channel to fluid flow led to increased secretion of regeneration-associated factors. Stimulation with relevant cytokines not only amplified the secretory response, but also induced cell-cycle entry of primary human hepatocytes (PHHs) embedded within the device. Further, we identified endothelial-derived mediators that are sufficient to initiate proliferation of PHHs in this context. Collectively, the data presented here underscore the importance of multicellular models that can recapitulate high-level tissue functions and demonstrate that the SHEAR device can be used to discover and validate conditions that promote human liver regeneration.
Topics: Cell Culture Techniques, Three Dimensional; Cytokines; Endothelial Cells; Hepatocytes; Humans; Liver; Liver Regeneration
PubMed: 35763565
DOI: 10.1073/pnas.2115867119 -
Aging Aug 2018The regenerative capacity of the liver after resection is reduced with aging. Recent studies on rodents revealed that both intracellular and extracellular factors are... (Review)
Review
The regenerative capacity of the liver after resection is reduced with aging. Recent studies on rodents revealed that both intracellular and extracellular factors are involved in the impairment of liver mass recovery during aging. Among the intracellular factors, age-dependent decrease of BubR1 (budding uninhibited by benzimidazole-related 1), YAP (Yes-associated protein) and SIRT1 (Sirtuin-1) have been associated to dampening of tissue reconstitution and inhibition of cell cycle genes following partial hepatectomy. Extra-cellular factors, such as age-dependent changes in hepatic stellate cells affect liver regeneration through inhibition of progenitor cells and reduction of liver perfusion. Furthermore, chronic release of pro-inflammatory proteins by senescent cells (SASP) affects cell proliferation suggesting that senescent cell clearance might improve tissue regeneration. Accordingly, young plasma restores liver regeneration in aged animals through autophagy re-establishment. This review will discuss how intracellular and extracellular factors cooperate to guarantee a proper liver regeneration and the possible causes of its impairment during aging. The possibility that an improvement of the liver regenerative capacity in elderly might be achieved through elimination of senescent cells autophagy or by administration of direct mitogenic agents devoid of cytotoxicity will also be entertained.
Topics: Aging; Animals; Cellular Senescence; Gene Expression Regulation; Liver; Liver Regeneration; Mice
PubMed: 30157472
DOI: 10.18632/aging.101524 -
Seminars in Thrombosis and Hemostasis Mar 2018Platelets are key players in thrombosis and hemostasis. Alterations in platelet count and function are common in liver disease, and may contribute to bleeding or... (Review)
Review
Platelets are key players in thrombosis and hemostasis. Alterations in platelet count and function are common in liver disease, and may contribute to bleeding or thrombotic complications in liver diseases and during liver surgery. In addition to their hemostatic function, platelets may modulate liver diseases by mechanisms that are incompletely understood. Here, we present clinical evidence for a role of platelets in the progression of chronic and acute liver diseases, including cirrhosis, acute liver failure, and hepatocellular carcinoma. We also present clinical evidence that platelets promote liver regeneration following partial liver resection. Subsequently, we summarize studies in experimental animal models that support these clinical observations, and also highlight studies that are in contrast with clinical observations. The combined results of clinical and experimental studies suggest that platelets may be a therapeutic target in the treatment of liver injury and repair, but the gaps in our understanding of mechanisms involved in platelet-mediated modulation of liver diseases call for caution in clinical application of these findings.
Topics: Blood Platelets; Humans; Inflammation; Liver Cirrhosis; Liver Diseases; Liver Regeneration
PubMed: 28898899
DOI: 10.1055/s-0037-1604091 -
Cellular and Molecular Gastroenterology... 2022Liver regeneration is a necessary but complex process involving multiple cell types besides hepatocytes. Mechanisms underlying liver regeneration after partial... (Review)
Review
BACKGROUND & AIMS
Liver regeneration is a necessary but complex process involving multiple cell types besides hepatocytes. Mechanisms underlying liver regeneration after partial hepatectomy and acute liver injury have been well-described. However, in patients with chronic and severe liver injury, the remnant liver cannot completely restore the liver mass and function, thereby involving liver progenitor-like cells (LPLCs) and various immune cells.
RESULTS
Macrophages are beneficial to LPLCs proliferation and the differentiation of LPLCs to hepatocytes. Also, cells expressing natural killer (NK) cell markers have been studied in promoting both liver injury and liver regeneration. NK cells can promote LPLC-induced liver regeneration, but the excessive activation of hepatic NK cells may lead to high serum levels of interferon-γ, thus inhibiting liver regeneration.
CONCLUSIONS
This review summarizes the recent research on 2 important innate immune cells, macrophages and NK cells, in LPLC-induced liver regeneration and the mechanisms of liver regeneration during chronic liver injury, as well as the latest macrophage- and NK cell-based therapies for chronic liver injury. These novel findings can further help identify new treatments for chronic liver injury, saving patients from the pain of liver transplantations.
Topics: Humans; Liver Regeneration; Interferon-gamma; Liver Diseases; Killer Cells, Natural; Macrophages
PubMed: 35738473
DOI: 10.1016/j.jcmgh.2022.05.014 -
Cell Reports Aug 2023Inadequate remnant volume and regenerative ability of the liver pose life-threatening risks to patients after partial liver transplantation (PLT) or partial hepatectomy...
Inadequate remnant volume and regenerative ability of the liver pose life-threatening risks to patients after partial liver transplantation (PLT) or partial hepatectomy (PHx), while few clinical treatments focus on safely accelerating regeneration. Recently, we discovered that supplementing 5-aminolevulinate (5-ALA) improves liver cold adaptation and functional recovery, leading us to uncover a correlation between 5-ALA metabolic activities and post-PLT recovery. In a mouse 2/3 PHx model, 5-ALA supplements enhanced liver regeneration, promoting infiltration and polarization of anti-inflammatory macrophages via P53 signaling. Intriguingly, chemokine receptor CX3CR1 functions to counterbalance these effects. Genetic ablation or pharmacological inhibition of CX3CR1 (AZD8797; phase II trial candidate) augmented the macrophagic production of insulin-like growth factor 1 (IGF-1) and subsequent hepatocyte growth factor (HGF) production by hepatic stellate cells. Thus, short-term treatments with both 5-ALA and AZD8797 demonstrated pro-regeneration outcomes superior to 5-ALA-only treatments in mice after PHx. Overall, our findings may inspire safe and effective strategies to better treat PLT and PHx patients.
Topics: Animals; Mice; Aminolevulinic Acid; Cell Proliferation; Disease Models, Animal; Hepatocytes; Insulin-Like Growth Factor I; Liver; Liver Regeneration
PubMed: 37578861
DOI: 10.1016/j.celrep.2023.112984